MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells

Abstract

Although the mechanisms by which glucose regulates insulin secretion from pancreatic β-cells are now well described, the way glucose modulates gene expression in such cells needs more understanding. Here, we demonstrate that MondoA, but not its paralog carbohydrate-responsive element–binding protein, is the predominant glucose-responsive transcription factor in human pancreatic β-EndoC-βH1 cells and in human islets. In high-glucose conditions, MondoA shuttles to the nucleus where it is required for the induction of the glucose-responsive genes arrestin domain–containing protein 4 (ARRDC4) and thioredoxin interacting protein (TXNIP), the latter being a protein strongly linked to β-cell dysfunction and diabetes. Importantly, increasing cAMP signaling in human β-cells, using forskolin or the glucagon-like peptide 1 mimetic Exendin-4, inhibits the shuttling of MondoA and potently inhibits TXNIP and ARRDC4 expression. Furthermore, we demonstrate that silencing MondoA expression improves glucose uptake in EndoC-βH1 cells. These results highlight MondoA as a novel target in β-cells that coordinates transcriptional response to elevated glucose levels.